Thyroxine-Metabolizing Rat Uridine Diphosphate-Glucuronosyltransferase 1A7 Is Regulated by Thyroid Hormone Receptor

• Published in: Endocrinology (Philadelphia) 2007-12, Vol.148 (12), p.6124-6133
• Main Authors: Emi, Yoshikazu, Ikushiro, Shin-ichi, Kato, Yoshihisa
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Biological and medical sciences; Cell Line, Tumor; Cercopithecus aethiops; Clearances; COS Cells; Fundamental and applied biological sciences. Psychology; Gene Expression - drug effects; Glucuronates - metabolism; Glucuronosyltransferase; Glucuronosyltransferase - genetics; Glucuronosyltransferase - metabolism; Homeostasis; Humans; Inactivation; Intracellular signalling; Isoenzymes; Isoenzymes - genetics; Isoenzymes - metabolism; Isoforms; Metabolic pathways; Molecular Sequence Data; Polychlorinated Dibenzodioxins - pharmacology; Promoter Regions, Genetic - genetics; Protein Binding; Proteins; Rats; Receptors; Receptors, Thyroid Hormone - genetics; Receptors, Thyroid Hormone - metabolism; Reporter gene; Retinoid X Receptor alpha - genetics; Retinoid X Receptor alpha - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; TCDD; Thyroid; Thyroid gland; Thyroid Hormones - blood; Thyroid Hormones - metabolism; Thyroxine; Thyroxine - metabolism; Transfection; UDP-glucuronosyltransferase; Uridine; Uridine Diphosphate - metabolism; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2007-0443

Exposure of rats to microsomal enzyme inducers perturbs thyroid hormone (TH) homeostasis through a variety of mechanisms. Glucuronidation is an important metabolic pathway for TH and is catalyzed by uridine diphosphate-dibenzo-glucuronosyltransferase (UGT) family proteins. Administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to rats markedly increases the biliary clearance of glucuronidated T4 and results in reduced plasma T4 levels. Determination of the UGT1 isoforms responsible for glucuronidation of T4 has yet to be conclusively established. We here provide evidence for the involvement of TCDD-inducible UGT1A7 in the glucuronidation of T4 and TH-controlled UGT1A7 expression. Among a number of rat UGT1 isoenzymes examined in this study, UGT1A7 was the most active in catalyzing glucuronidation of T4. Expression of UGT1A7 was positively regulated by T4 through specific binding of TH receptor-retinoid X receptor heterodimers to a DR-5 sequence located between −109 and −93 in the UGT1A7 promoter. Overproduction of UGT1A7 protein decreased T4 responsiveness of a reporter gene containing the T4-responsive UGT1A7 promoter sequence. These results raise the possibility that UGT1A7 plays a key role in the glucuronidation of T4 leading to inactivation of T4, functioning via feedback regulation to control T4 levels in an autoregulatory manner, and that T4 regulates its own metabolism and subsequent clearance from cells. Our findings also predict that accumulation of TCDD-inducible UGT1A7 proteins in TH-target cells might disrupt the TH signaling by lowering the intracellular pool of T4.